Objective Prior work has shown that quantitative EEG and evoked potentials (EPs) may be useful as objective measures of brain function for CDKL5 deficiency disorder (CDD), a developmental and epileptic encephalopathy associated with pathogenic variants in CDKL5. The current study builds on this work by examining associations between EEG/EP parameters and CDD-specific symptom severity in a large, representative cohort of individuals with CDD. Methods Resting EEG and visual and auditory EPs were acquired from 77 participants with CDD in a multi-site study designed to enhance clinical trial readiness for CDD. The statistical analysis evaluated associations between the EEG/EP parameters and validated CDD-specific measures of clinical severity. Results Resting EEG 1/f slope and power ratios were significantly associated with the clinical measures such that greater EEG background slowing correlated with greater symptom severity. In contrast, neither visual nor auditory EP measures were significantly associated with clinical severity in this cohort. Conclusions The results underscore the potential utility of resting EEG parameters to serve as objective measures of clinical severity and brain function for CDD.Significance: Future studies should continue to refine resting EEG as a biomarker to facilitate therapeutic development for CDD, as well as test new methods for the acquisition and analysis of EPs in this population.

BACKGROUND: FOXG1 syndrome is a severe genetic neurodevelopmental disorder characterized by intellectual and developmental disabilities (IDD), postnatal microcephaly, epilepsy, and movement disorder. With the advent of molecular therapies, establishing the natural history of FOXG1 syndrome is critical to enable clinical trial readiness. However, traditional study designs are challenging to implement for rare disorders without significant burden to participants. METHODS: The study population included 101 children and adults with (likely) pathogenic variants in or involving FOXG1 (ages 0.4 - 34.8 years). Participant medical records underwent systematic annotation and harmonization of recorded clinical phenotypes, interventions, and outcomes through use of a patient-centric real-world data (RWD) platform. Retrospective medical record data were paired with prospective administration of validated measures of development and behavior, including the Vineland-3, the Aberrant Behavior Checklist, and the Children’s Sleep Habits Questionnaire. Descriptive and inferential statistics were employed to characterize longitudinal phenotypes and to explore genotype-phenotype correlations. RESULTS: Through systematic evaluation of 101 people with FOXG1 syndrome, we generated a robust dataset encompassing >40,000 annotated clinical terminology concepts that represent >770 cumulative patient data years. Core clinical phenotypes include IDD, gastrointestinal disorders, strabismus, epilepsy, movement disorders, and sleep problems. The FOXG1 syndrome behavioral phenotype is characterized by irritability, including aggressive behaviors, stereotypies, social withdrawal, and lethargy; in those with missense variants, features of autism spectrum disorders are also reported. Data derived from both medical records and validated measures confirm and expand upon previously described genotype-phenotype correlations, whereby truncating variants are associated with greater limitations across motor and communication domains, as well as increased frequency of core FOXG1 syndrome phenotypes. Further, individuals with truncating variants had higher scores on a composite measure of FOXG1 syndrome severity, which persists when modeled longitudinally. Employing the same composite measure, we demonstrate that FOXG1 syndrome is a static encephalopathy without evidence of neurodegeneration. CONCLUSIONS: By combining retrospective RWD with prospective survey administration in a large sample population, we establish the natural history of FOXG1 syndrome and highlight candidate clinical endpoints for use in clinical trials, including quantitative evaluations of communication and movement disorders.

BACKGROUND AND OBJECTIVES:Developmental impairment is common in individuals with SCN2A-related disorders, although descriptions are limited. We aimed to determine trajectories and outcomes of development and adaptive function. METHODS:This was a mixed retrospective cross-sectional study of individuals from an international SCN2A Natural History Study, who had neurologic/neurodevelopmental disorders due to an SCN2A variant. Individuals with SCN2A intragenic variants were grouped into early-onset (EO) and late-onset (LO) phenotypic groups; those with SCN2A-containing 2q24.3 copy number variants (CNVs) were considered separately. We collected medical and developmental history from parents/caregivers and medical records. Adaptive function and behavior were characterized using functional classification system levels and Vineland Adaptive Behavior Scales-3 (VABS-3) Parent/Caregiver Form. We repeated analyses on individuals with variants known to result in gain-of-function (GOF, typically EO phenotypes) or loss-of-function (LOF, typically LO phenotypes). RESULTS:A total of 100 individuals (age 0.1-21.9 years, 39% female) were studied. Phenotypic groups were EO (n = 44), LO (n = 48), and 2q24.3 CNV (n = 8). Developmental delay/intellectual disability was present in 91 of 100, and 23 of 80 individuals (29%) older than 2 years had autism spectrum disorder. Of people older than the typical age for skill attainment, 59 of 95 (62%) could sit and 48 of 88 (55%) could walk. In addition, 27 of 86 individuals (31%) spoke more than 1-5 single words, and 24 of 74 (32%) followed two-step commands. Median VABS-3 Adaptive Behavior Composite (ABC) scores were as follows: the EO phenotypic group had a score of 56 (range 21-110), the LO phenotypic group had a score of 45 (range 20-89), and 5 of 6 with a 2q24.3 CNV had an ABC score of <45. The EO phenotypic group had 3 distinct subgroups, consistent with "benign," "intermediate," and "severe" definitions previously published. The LO phenotypic group showed a continuum of severity, without distinct clusters. However, clinically relevant differences in motor function were evident when subgrouped by seizure-onset age; a lower proportion with earlier seizure onset (age <18 months) were independently ambulant than those with later onset or no seizures (5/15 [33%] vs 10/12 [83%] vs 14/15 [93%], p < 0.01). Analyses of individuals with confirmed GOF/LOF variants (n = 57) showed similar results to the EO/LO analyses. DISCUSSION:The spectrum of developmental impairments and adaptive function in SCN2A-related disorders is extremely broad. Phenotypic subgroups provide prognostic information and critically inform clinical trial design.

BACKGROUND:CDKL5 deficiency disorder (CDD) is a rare developmental and epileptic encephalopathy (DEE) associated with multiple impairments and comorbidities. Outcome measures for disease-modifying clinical trials for DEEs should measurably capture a spectrum of caregiver priorities and be externally validated. METHODS:The International CDKL5 Clinical Research Network was the data source for this observational study. A Structural Equation Model was constructed with latent, exogenous variables related to observed clinical features to calculate a global severity score from the following assessments: the CDKL5 Clinical Severity Assessment-Clinician and -Caregiver, Communication and Symbolic Behavior Scales Developmental Profile Infant Toddler Checklist and the Sleep Disturbance Scale for Children. Quantitative EEG power was measured as a biomarker. The Quality of Life Inventory-Disability measured quality of life. RESULTS:Acceptable fit statistics for models were obtained using data from 206 subjects (median [range] age 6.8 [3 months to 40] years). Motor and communication measures were the most important weighted contributors to the global severity score which correlated well with the biomarker and quality of life to support external validation. CONCLUSIONS:The resultant global severity score provided evidence that the assessments formed a coherent set of measures that reliably and meaningfully captured the diversity of severity in CDD. The models illustrated how the symptoms form a measurable network of relationships which may be suitable as an outcome measure for CDD and DEEs more broadly in clinical trials.

Knowledge of the natural history of CDKL5 deficiency disorder (CDD) is limited to the results of cross-sectional analysis of largely pediatric cohorts. Assessment of outcomes in adulthood is critical for clinical decision-making and future precision medicine approaches but is challenging because of the diagnostic gap and duration of follow-up that would be required for prospective studies. We aimed to delineate the natural history retrospectively from adulthood. We analyzed clinical data about an international cohort of 67 adults with CDD. We analyzed demographic, phenotypic, CDKL5 Developmental Score (CDS), and treatment data, and tested associations with genetic factors, sex, and a positive or negative history of neonatal seizures, as an early predictor of prognosis. All but one of 67 adults (55 females, median age of 24 years at last follow-up) had epilepsy, typically beginning with epileptic spasms or tonic seizures before 4 months of age. Focal-onset and non-motor seizures emerged later. Fewer than a third had been documented as having bilateral tonic-clonic seizures or status epilepticus. Seizures often improved with age, but 73% had never experienced more than 6 months of seizure-freedom. Clobazam, sodium valproate, and lamotrigine were the most frequently prescribed antiseizure medications, but no specific treatment demonstrated superiority. Common comorbidities included movement disorders, visual impairment, sleep disorders, constipation, and scoliosis. All participants had intellectual disability, 75% had not acquired speech and 45% had regressed developmentally. 16% never achieved any CDS skill, but most attained at least three, and 28% attained six or all seven. By adulthood, half of those who had achieved any CDS skill retained all their CDS skills. The skills most frequently lost were independent walking and standing. Those with a history of neonatal seizures tended to attain fewer CDS skills and were more likely to have abnormal muscle tone in adulthood, atrioventricular conduction delay, and potential complications of their illness and treatment. Individuals carrying missense variants attained more CDS skills than those with other variants and were more likely to lose skills in adulthood and develop anxiety, possibly reflecting the limited neurodevelopment of those with non-missense variants, who manifested a more multisystemic disorder. In summary, retrospective data from adulthood elucidates the evolution of symptoms, variation in developmental outcomes, and the treatment landscape in CDKL5 deficiency disorder. Presence a non-missense variants or a history of neonatal seizures indicates a more complex disorder and lower developmental trajectory. Our findings will inform management decisions, prognostication, and the design of clinical trials in CDKL5 Deficiency Disorder.

Loss of function variants in the Cyclin-dependent kinase-like 5 gene (CDKL5) causes CDKL5 deficiency disorder (CDD). Most cases of CDD are due to a de novo missense or truncating variants. The CDKL5 gene was discovered in 1998 as part of the genomic mapping of the chromosome Xp22 region that led to the discovery of the serine-threonine kinases STK9. Since then, there have been significant advancements in the description of the disease in humans, the understanding of the pathophysiology, and the management of the disease. There have been many lessons learned since the initial description of the condition in humans in 2003. In this article, we will focus on pathophysiology, clinical manifestations, with particular focus on seizures because of its relevance to the medical practitioners and researchers and guidelines for management. We finalize the manuscript with the voice of the parents and caregivers, as discussed with the 2019 meeting with the Food and Drug Administration.

OBJECTIVE:Lead time to treatment (clinical onset of epileptic spasms [ES] to initiation of appropriate treatment) is known to predict outcomes in infantile epileptic spasms syndrome (IESS). Timing the clinical onset of ES is crucial to establish lead time. We investigated how often ES onset could be established to the nearest week. We aimed to (1) ascertain the exact date or estimate the nearest week of ES onset and (2) compare clinical/demographic factors between patients where date of ES onset was determined or estimated to the nearest week and patients whose date of ES onset could not be estimated to the nearest week. Reasons for difficulties in estimating date of ES onset were explored.METHODS:Retrospective chart review of new onset IESS patients (January 2019-May 2022) extracted the date or week of the clinical onset of ES. Predictors of difficulty in date of ES onset estimation to the nearest week were examined by regression analysis. Sources contributing to difficulties determining date of ES onset were assessed after grouping into categories (provider-, caregiver-, disease-related).RESULTS:Among 100 patients, date of ES onset was estimated to the nearest week in 47%. On univariable analysis, age at diagnosis (p = .021), development delay (p = .007), developmental regression/stagnation (p = .021), ES intermixed with other seizures (p = .011), and nonclustered ES at onset (p = .005) were associated with difficulties estimating date of ES onset. On multivariable analysis, failure to establish date of ES onset was related to ES intermixed with other seizures (p = .004) and nonclustered ES at onset (p = .003). Sources contributing to difficulties determining date of ES onset included disease-related factors (ES characteristics, challenges interpreting electroencephalograms) and provider/caregiver-related factors (delayed diagnosis).SIGNIFICANCE:Difficulties with estimation of lead time (due to difficulties timing ES onset) can impact clinical care (prognostication), as even small increments in lead time duration can have adverse developmental consequences.

SCN2A encodes a voltage-gated sodium channel (designated NaV1.2) vital for generating neuronal action potentials. Pathogenic SCN2A variants are associated with a diverse array of neurodevelopmental disorders featuring neonatal or infantile onset epilepsy, developmental delay, autism, intellectual disability and movement disorders. SCN2A is a high confidence risk gene for autism spectrum disorder and a commonly discovered cause of neonatal onset epilepsy. This remarkable clinical heterogeneity is mirrored by extensive allelic heterogeneity and complex genotype-phenotype relationships partially explained by divergent functional consequences of pathogenic variants. Emerging therapeutic strategies targeted to specific patterns of NaV1.2 dysfunction offer hope to improving the lives of individuals affected by SCN2A-related disorders. This Element provides a review of the clinical features, genetic basis, pathophysiology, pharmacology and treatment of these genetic conditions authored by leading experts in the field and accompanied by perspectives shared by affected families. This title is also available as Open Access on Cambridge Core.

Background: CDKL5 deficiency disorder (CDD) is an early-onset developmental and epileptic encephalopathy. While a subset of individuals is believed to experience comorbid behavioral disorders, none have reported well-defined affective disorders. Though there is a documented association between epilepsy and mood disorders, they may go undetected in the CDD population due to difficulty assessing mood in the presence of severe/profound intellectual disability and disease-related sleep dysregulation. We aimed to identify the clinical characteristics of an individual with CDD who presented with a mood disorder falling outside this expected behavioral phenotype. Case Presentation: We identified one 22-year-old female with CDD diagnosed with unspecified bipolar disorder at 18 years of age. Family history was noncontributory. At diagnosis, she had fluctuations in mood, characterized by periods of elated affect, increased energy and vocalizations, hypertonia, and insomnia lasting 3-4 days alternating with periods of depressed affect, irritability, hypotonia, and excessive sleep lasting for up to one month. She had experienced frequent mood swings and sleep dysregulation from early childhood, and by early adulthood the duration of “up” and “down” periods fell in the range specified in the DSM-5 bipolar disorder criteria. Trazodone and suvorexant did not alleviate sleep related symptoms. Her epilepsy was well controlled on lamotrigine monotherapy since early childhood. Though lamotrigine treatment has had no psychiatric benefit despite its known mood stabilizing properties, aripiprazole has been effective in reducing severity and frequency of fluctuations between hypomania and depression. Conclusions: While sleep and behavioral disorders fall within the expected phenotype for CDD, this is the first report of bipolar disorder. Careful attention to patterns of sleep and behavior that may indicate mood cycling in this population is required, particularly in the setting of limited communication and functional abilities.

OBJECTIVE:The CDKL5 Clinical Severity Assessment (CCSA) is a comprehensive, content-validated measurement tool capturing the diverse challenges of cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD), a genetically caused developmental epileptic encephalopathy (DEE). The CCSA is divided into clinician-reported (CCSA-Clinician) and caregiver-reported (CCSA-Caregiver) assessments. The aim of this study was to evaluate the factor structure of these measures through confirmatory factor analysis (CFA) and evaluate their validity and reliability. METHODS:Participants were recruited from the International CDKL5 Clinical Research Network to take part in an in-clinic CCSA-Clinician evaluation (n = 148) and/or complete the CCSA-Caregiver questionnaire (n = 198). CFA was used to determine domains, and factor loadings and validity were assessed. For the CCSA-Clinician, inter-rater reliability was assessed by nine CDD experienced clinicians via 14 pre-recorded evaluations. Eight clinicians re-viewed and re-scored the videos after 4 weeks to evaluate intra-rater reliability. The CCSA-Caregiver was completed on a second occasion by 34 caregivers after 2-4 weeks to assess test-retest reliability. RESULTS:CFA resulted in three domains for the CCSA-Clinician (motor and movement, communication, vision) and four domains for the CCSA-Caregiver (seizures, behavior, alertness, feeding), with good item loadings across both measures. Structural statistics, internal consistency, discriminant validity, and reliability were satisfactory for both measures, and scores were consistent between known groups. SIGNIFICANCE:This study provides strong evidence that the CCSA measures are suitable to assess the clinical severity of individuals with CDD, supporting their use in clinical trials. Further evaluation of responsiveness to change in a longitudinal assessment is planned. Use may also be appropriate in similar DEEs but would require validation in those populations.

CDKL5 deficiency disorder presents as a challenging condition with early-onset refractory seizures, severe developmental delays, and a range of other neurological symptoms. Our study aimed to explore the benefits and side effects of anti-seizure medications (ASMs) in managing seizures among individuals with CDKL5 deficiency disorder, drawing on data from the International CDKL5 Disorder Database. Data for this retrospective cohort study were obtained from the International CDKL5 Disorder Database, which contains responses from a baseline questionnaire administered between 2012 and 2022 and a follow-up questionnaire administered between 2018 and 2019. Families of eligible individuals were asked to provide information on ASMs that were previously and currently taken, the dose prescribed, the age at starting the medications, and the age at discontinuation for past medications. The outcome variables of interest were perceived seizure-related benefits for the current and past use of ASMs and caregiver-reported side effects. Rescue medications and infrequently used ASMs were excluded from the analysis. Descriptive statistics were used to summarise the characteristics of the study population. The study included 399 children and adults with CDKL5 deficiency disorder, descriptively analysing the perceived benefits and side effects of 23 unique ASMs based on caregiver reports. The study identified levetiracetam, topiramate, sodium valproate, vigabatrin, phenobarbital and clobazam as the most used ASMs. Notably, cannabidiol showed highly beneficial outcomes with few side effects, whereas levetiracetam and phenobarbital exhibited less favourable benefit-to-side-effect ratios. Dual therapy involving sodium valproate and levetiracetam was only used a small number (n = 5) of times but appeared effective in reducing seizure activity with relatively few side effects. Compared with monotherapy, polytherapy had a relatively higher likelihood of reported side effects than benefits. The study, leveraging a large sample size that exceeds that of previous research, emphasises the complex nature of seizure management in CDKL5 deficiency disorder. Our findings underscore the necessity of ongoing research to optimise treatment strategies, considering both the efficacy of seizure control and the potential for adverse effects. The study also points to the need for future investigations into the therapeutic potential of emerging treatments such as ganaxolone and the unresolved efficacy of cannabis products in seizure management.

Pathogenic variants in the cyclin-dependent kinase-like 5 (CDKL5) gene are associated with CDKL5 deficiency disorder (CDD), a severe X-linked developmental and epileptic encephalopathy. Deletions affecting the 5 ' untranslated region (UTR) of CDKL5, which involve the noncoding exon 1 and/or alternatively spliced first exons (exons 1a-e), are uncommonly reported. We describe genetic and phenotypic characteristics for 15 individuals with CDKL5 partial gene deletions affecting the 5 ' UTR. All individuals presented characteristic features of CDD, including medically refractory infantile-onset epilepsy, global developmental delay, and visual impairment. We performed RNA sequencing on fibroblast samples from three individuals with small deletions involving exons 1 and/or 1a/1b only. Results demonstrated reduced CDKL5 mRNA expression with no evidence of expression from alternatively spliced first exons. Our study broadens the genotypic spectrum for CDD by adding to existing evidence that deletions affecting the 5 ' UTR of the CDKL5 gene are associated with the disorder. We propose that smaller 5 ' UTR deletions may require additional molecular testing approaches such as RNA sequencing to determine pathogenicity.

Sleep difficulties are common in CDKL5 deficiency disorder, a developmental and epileptic encephalopathy. This study evaluated the factor structure of the Disorders of Initiating and Maintaining Sleep (DIMS), Disorders of Excessive Somnolence (DOES), and Sleep Breathing Disorders domains of the Sleep Disturbance Scale for Children for CDKL5 deficiency disorder. A cross-sectional psychometric study design was used. Data were collected for 125 individuals aged 3 years or older who attended a United States Centers of Excellence clinic or registered with the International CDKL5 Disorder Database. The median age was 10.3 years (range 3.2–40.7 years) and 105 (84

Genetic variants in KCNQ2 are associated with a range of epilepsies, from self- limited (familial) neonatal-infantile epilepsy to developmental and epileptic encephalopathy (DEE). We retrospectively reviewed clinical data from eight patients with KCNQ2-related DEE who were treated with ezogabine. Treatment was initiated at a median age of 8 months (range, 7 weeks to 2.5 years) and continued for a median of 2.6 years (range, 7 months to 4.5 years). Five individuals had daily seizures at baseline and experienced at least 50% seizure reduction with treatment, sustained in four. One individual with two to four yearly seizures improved to rare events. Two individuals were seizure-free; treatment targeted cognition and development. Developmental improvements were reported in all eight patients. Weaning of ezogabine was associated with increased seizure frequency (N = 4), agitation and irritability (N = 2), poor sleep (N = 1), and developmental regression (N = 2). These data suggest that treatment with ezogabine is effective at reducing seizure burden and is associated with improved development. Minimal side effects were observed. Weaning was associated with increased seizures and behavioral disturbances in a subset. An approach targeting potassium channel dysfunction with ezogabine is warranted in patients with KCNQ2-related DEE.

Background: CDKL5 Deficiency Disorder (CDD) is a severe X-linked developmental and epileptic encephalopathy. Existing developmental outcome measures have floor effects and cannot capture incremental changes in symptoms. We modified the caregiver portion of a CDD clinical severity assessment (CCSA) and assessed content and response-process validity. Methods: We conducted cognitive interviews with 15 parent caregivers of 1-39-year-old children with CDD. Caregivers discussed their understanding and concerns regarding appropriateness of both questions and answer options. Item wording and questionnaire structure were adjusted iteratively to ensure questions were understood as intended. Results: The CCSA was refined during three rounds of cognitive interviews into two measures: (1) the CDD Developmental Questionnaire - Caregiver (CDQ-Caregiver) focused on developmental skills, and (2) the CDD Clinical Severity Assessment - Caregiver (CCSA-Caregiver) focused on symptom severity. Branching logic was used to ensure questions were age and skill appropriate. Initial pilot data (n = 11) suggested no floor effects.

OBJECTIVE:We aimed to assess the treatment response of infantile-onset epileptic spasms (ES) in CDKL5 deficiency disorder (CDD) vs other etiologies. METHODS:We evaluated patients with ES from the CDKL5 Centers of Excellence and the National Infantile Spasms Consortium (NISC), with onset from 2 months to 2 years, treated with adrenocorticotropic hormone (ACTH), oral corticosteroids, vigabatrin, and/or the ketogenic diet. We excluded children with tuberous sclerosis complex, trisomy 21, or unknown etiology with normal development because of known differential treatment responses. We compared the two cohorts for time to treatment and ES remission at 14 days and 3 months. RESULTS:We evaluated 59 individuals with CDD (79% female, median ES onset 6 months) and 232 individuals from the NISC database (46% female, median onset 7 months). In the CDD cohort, seizures prior to ES were common (88%), and hypsarrhythmia and its variants were present at ES onset in 34%. Initial treatment with ACTH, oral corticosteroids, or vigabatrin started within 1 month of ES onset in 27 of 59 (46%) of the CDD cohort and 182 of 232 (78%) of the NISC cohort (p < .0001). Fourteen-day clinical remission of ES was lower for the CDD group (26%, 7/27) than for the NISC cohort (58%, 106/182, p = .0002). Sustained ES remission at 3 months occurred in 1 of 27 (4%) of CDD patients vs 96 of 182 (53%) of the NISC cohort (p < .0001). Comparable results were observed with longer lead time (≥1 month) or prior treatment. Ketogenic diet, used within 3 months of ES onset, resulted in ES remission at 1 month, sustained at 3 months, in at least 2 of 13 (15%) individuals with CDD. SIGNIFICANCE:Compared to the broad group of infants with ES, children with ES in the setting of CDD often experience longer lead time to treatment and respond poorly to standard treatments. Development of alternative treatments for ES in CDD is needed.

Background Developing biomarkers is a priority for drug development for all conditions, but vital in the rare neurodevelopmental disorders where sensitive outcome measures are lacking. We have previously demonstrated the feasibility and tracking of evoked potentials to disease severity in Rett syndrome and CDKL5 deficiency disorder. The aim of the current study is to characterize evoked potentials in two related developmental encephalopathies, MECP2 duplication syndrome and FOXG1 syndrome, and compare across all four groups to better understand the potential of these measures to serve as biomarkers of clinical severity for the developmental encephalopathies. Methods Visual and auditory evoked potentials were acquired from participants with MECP2 duplication syndrome and FOXG1 syndrome across five sites of the Rett Syndrome and Rett-Related Disorders Natural History Study. A group of age-matched individuals (mean = 7.8 years; range = 1–17) with Rett syndrome, CDKL5 deficiency disorder, and typically-developing participants served as a comparison group. The analysis focused on group-level differences as well as associations between the evoked potentials and measures of clinical severity from the Natural History Study. Results As reported previously, group-level comparisons revealed attenuated visual evoked potentials (VEPs) in participants with Rett syndrome ( n = 43) and CDKL5 deficiency disorder ( n = 16) compared to typically-developing participants. VEP amplitude was also attenuated in participants with MECP2 duplication syndrome ( n = 15) compared to the typically-developing group. VEP amplitude correlated with clinical severity for Rett syndrome and FOXG1 syndrome ( n = 5). Auditory evoked potential (AEP) amplitude did not differ between groups, but AEP latency was prolonged in individuals with MECP2 duplication syndrome ( n = 14) and FOXG1 syndrome ( n = 6) compared to individuals with Rett syndrome ( n = 51) and CDKL5 deficiency disorder ( n = 14). AEP amplitude correlated with severity in Rett syndrome and CDKL5 deficiency disorder. AEP latency correlated with severity in CDKL5 deficiency disorder, MECP2 duplication syndrome, and FOXG1 syndrome. Conclusions There are consistent abnormalities in the evoked potentials in four developmental encephalopathies some of which correlate with clinical severity. While there are consistent changes amongst these four disorders, there are also condition specific findings that need to be further refined and validated. Overall, these results provide a foundation for further refinement of these measures for use in future clinical trials for these conditions.

OBJECTIVE:In the placebo-controlled, double-blind phase of the Marigold study (NCT03572933), ganaxolone significantly reduced major motor seizure frequency (MMSF) in patients with cyclin-dependent kinase-like 5 deficiency disorder (CDD). We report 2-year safety and clinical outcomes data from the open-label extension (OLE) phase of Marigold. METHODS:Patients with CDD who completed the double-blind phase were eligible to continue in the OLE. Efficacy assessments included MMSF reduction from prerandomization baseline, responder rates, and Clinical Global Impression-Improvement scores, including assessment of seizure intensity and duration (CGI-CSID). Safety assessments included treatment-emergent adverse events (TEAEs) and TEAEs leading to discontinuation. RESULTS:Of 101 patients who enrolled in Marigold, 88 (87.1%) entered the OLE (median age = 5 years, 79.5% female). Median 28-day MMSF at baseline was 50.6. At 2 years in the OLE (months 22-24), MMSF was reduced by a median of 48.2% (n = 50); when missing data were imputed, median reduction in MMSF was 43.8% using a mixed effects model and 27.4% using a last observation carried forward model. During months 22-24, 23 of 50 (46.0%) patients experienced reductions in MMSF of ≥50%; 12 of 50 (24.0%) patients experienced MMSF reductions of ≥75%. During months 22-24, 40 of 49 (81.6%) patients were rated by caregivers as having improvement in seizure-related outcomes based on CGI-CSID scores. Thirty-seven patients discontinued ganaxolone due to lack of efficacy (n = 13), withdrawal by caregiver (n = 12), adverse event (n = 10), physician decision (n = 1), or death (n = 1; unrelated to study drug). The most common treatment-related TEAEs were somnolence (17.0%), seizure (11.4%), and decreased appetite (5.7%). Patients reported serious TEAEs (n = 28, 31.8%); those reported in ≥3% of patients were seizure (n = 6), pneumonia (n = 5), acute respiratory failure (n = 3), aspiration pneumonia (n = 3), and dehydration (n = 3). SIGNIFICANCE:Sustained reductions in MMSF at 2 years in the OLE support the efficacy of ganaxolone in seizures associated with CDD. Safety findings in the OLE were consistent with the double-blind phase.

AIM To differentiate phenotypic features of individuals with CDKL5 deficiency disorder (CDD) from those of individuals with other infantile-onset epilepsies. METHOD We performed a retrospective cohort study and ascertained individuals with CDD and comparison individuals with infantile-onset epilepsy who had epilepsy gene panel testing. We reviewed records, updated variant classifications, and compared phenotypic features. Wilcoxon rank-sum tests and χ2 or Fisher's exact tests were performed for between-cohort comparisons. RESULTS We identified 137 individuals with CDD (110 females, 80.3%; median age at last follow-up 3 year 11 months) and 313 individuals with infantile-onset epilepsies (156 females, 49.8%; median age at last follow-up 5 years 2 months; 35% with genetic diagnosis). Features reported significantly more frequently in the CDD group than in the comparison cohort included developmental and epileptic encephalopathy (81% vs 66%), treatment-resistant epilepsy (95% vs 71%), sequential seizures (46% vs 6%), epileptic spasms (66% vs 42%, with hypsarrhythmia in 30% vs 48%), regression (52% vs 29%), evolution to Lennox-Gastaut syndrome (23% vs 5%), diffuse hypotonia (72% vs 36%), stereotypies (69% vs 11%), paroxysmal movement disorders (29% vs 17%), cerebral visual impairment (94% vs 28%), and failure to thrive (38% vs 22%). INTERPRETATION CDD, compared with other suspected or confirmed genetic epilepsies presenting in the first year of life, is more often characterized by a combination of treatment-resistant epilepsy, developmental and epileptic encephalopathy, sequential seizures, spasms without hypsarrhythmia, diffuse hypotonia, paroxysmal movement disorders, cerebral visual impairment, and failure to thrive. Defining core phenotypic characteristics will improve precision diagnosis and treatment.